Tlr3, Toll-like receptor 3, is a member of the TLR family. It is crucial for mediating the transcriptional induction of type I interferons (IFNs), proinflammatory cytokines, and chemokines, thus establishing an antiviral host response. TLR3 is unique among TLR family members as the only RNA sensor completely reliant on the Toll-interleukin-1 receptor (TIR)-domain-containing adaptor-inducing IFN-β (TRIF) [1].

In chronic neuropathic pain mouse models, TLR3 knockout (KO) mice showed improved cognitive function, reduced levels of inflammatory cytokines and neuronal apoptosis, and attenuated injury to hippocampal neuroplasticity compared to wild-type mice. This indicates that extracellular RNAs (exRNAs), especially double-stranded RNAs (dsRNAs) in chronic neuropathic pain, activate TLR3, initiating downstream inflammatory and apoptotic signaling, and contributing to cognitive impairment [2]. In lung metastasis studies, TLR3-deficient mice had reduced lung metastasis in spontaneous metastatic models. Tumor exosomal RNAs activate TLR3 in lung epithelial cells, inducing chemokine secretion and neutrophil recruitment, promoting lung pre-metastatic niche formation [3].

In conclusion, Tlr3 plays significant roles in antiviral innate immune responses, cognitive function in the context of chronic neuropathic pain, and cancer metastasis. Gene knockout mouse models have been instrumental in revealing these functions, contributing to our understanding of related disease mechanisms and potentially guiding the development of new treatment strategies for viral diseases, cognitive impairment, and cancer metastasis.